AD is a progressive neurodegenerative disorder that gradually damages the neurons in regions of the brain involved in memory, learning and reasoning.
The diagnostic of AD is currently post mortem and consists in checking the presence of extracellular accumulation of amyloid β (Aβ) peptides forming amyloid deposits in the brain parenchyma. AD is currently incurable. AD is a multifactorial disease. The cause for most Alzheimer's cases is still essentially unknown (except for 1% to 5% of cases where genetic mutations have been identified).
Several competing hypotheses exist trying to explain the cause of AD.
On the one hand it has been proposed that amyloid beta (Aβ) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the Alzheimer genetic mutations located on APP gene, for the APP on Chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome), who have an extra copy of the APP gene, almost universally exhibit AD by 40 years of age. APOE4, the major genetic risk factor for AD, also leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, the amyloid cascade hypothesis places the amyloid production, oligomerization, aggregation and synaptoxicity at the center of Alzheimer etiopathogenesis. Further evidence comes from the finding that transgenic mice, which express a mutant form of the human APP gene, develop fibrillar amyloid deposits and Alzheimer's-like brain pathology with spatial learning deficits.
On the other hand, AD is also known as a tauopathy. In tauopathies, abnormally and hyperphosphorylated tau protein isoforms aggregate into fibrillar structures within neurons to form the so-called neurofibrillary tangles (NFTs). The precise mechanism of tangle formation is not completely understood but mutations of tau gene—also called MAPT for microtubule-associated protein tau—are associated with the development of a tauopathy named Frontotemporal Dementia with Parkinsonism linked to chromosome 17.
Neurodegeneration results in the progressive loss of structure or function of neurons, leading to their death. Many neurodegenerative diseases, including Parkinson's (PD), Alzheimer's, Huntington's (HD) diseases, amyotrophic lateral sclerosis (ALS) with frontotemporal dementia, inclusion body myopathy with Paget's bone disease and frontotemporal dementia (IBMPFD) occur as a result of neurodegenerative processes. As research progresses, many similarities appear relating these diseases to each other in terms of common physiopathological hallmarks from the subcellular level to the clinical symptoms observed in patients. Noteworthy, the whole spectrum of these neurodegenerative diseases are associated to the accumulation and aggregation of unfolded or mis-folded proteins such as synuclein, amyloid peptide, microtubule-associated protein tau, huntingtin, TDP-43, FUS/TLS etc.
The degradation of altered or pathologically mis-folded proteins is a complex phenomenon, which takes many cellular paths and is likely deregulated in a large number of pathologies. At the crossroads of cellular systems of protein degradation such as endosome/lysosome, endoplasmic reticulum associated-degradation, autophagy and ubiquitin-proteasome system, VCP (Valosin Containing Protein), also referred as p97 or CDC48, is a new therapeutic target for the treatment of neurodegenerative diseases and cancers. VCP is a member of AAA+/ATPase enzyme family (ATPases are associated with various cellular activities) and is involved in a growing number of cellular mechanims: cellular division, organelle biogenesis, nucleus membrane formation, DNA repair, transport and vesicules fusion, protein degradation and suppression of protein aggregates. It is associated with cofactors such as with HSP90, Ufd1 or Np14. Its importance has been demonstrated in several diseases. In particular, mutations in VCP/p97 gene have been shown to be linked to IBMPFD and some familial ALS. Moreover, several neurodegenerative diseases are associated to protein degradation dysfunction (Nixon R A, Yang D S, Lee J Y. Autophagy, 2008, 4, 590-99). The possible linkage of VCP to the AD-relevant protein Tau was recently proposed (Dolan P J, Jin Y N, Hwang W, Johnson G V. FEBS Lett, 2011, 585, 3424-9; Abisambra JF1, Jinwal U K, Blair L J, O'Leary J C 3rd, Li Q, Brady S, Wang L, Guidi C E, Zhang B, Nordhues B A, Cockman M, Suntharalingham A, Li P, Jin Y, Atkins C A, Dickey C A. J Neurosci. Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. 2013 May 29; 33(22):9498-507. doi: 10.1523/JNEUROSCI.5397-12.2013). VCP/p97, which is essential for the maturation of ubiquitin containing autophagosomes, is a potential therapeutic target of choice for the treatment of neurodegenerative diseases.
Document WO 2006/051489 describes the use of 1,4-bis(3-aminoalkyl)piperazine derivatives in the treatment of neurodegenerative diseases, particularly in the treatment of AD. The compounds disclosed in the afore-mentioned document are able to a) increase the carboxy-terminal fragments of APP (APP-CTFs) which all in common possess the last 50 amino acids of APP, and especially those having potential physiological activities, such as the α-stubs (APP-CTF alpha) and the ε-stubs (APP-CTF gamma or AICD for APP intra cellular domain), b) increase the soluble fragment sAPPα, c) decrease the production of neurotoxic by-products of APP, i.e. 3-amyloid (Aβ) peptides, especially in their form x-42 and d) without modifying the APP expression and in the absence of neurotoxicity.
An object of the present invention is to provide new compounds that can be useful as drugs, especially for the treatment of diseases related with APP disorder, for the treatment of tauopathies and more particularly for the treatment of neurodegenerative diseases such as AD, Lewy body disease, Down syndrome, amyloid angiopathy, PD, ALS, frontotemporal lobar degeneration and IBMPFD.
Another object of the present invention is to provide compounds having an effect on Tau pathology.
Another object of the present invention is to provide compounds having a biological activity in at least one of the afore-mentioned mechanisms a) to d) as regard to β-amyloid (Aβ) peptides and the afore-mentioned mechanisms as regards tau pathology.
Another object is to provide compounds useful as drugs, especially for the treatment of the afore-mentioned diseases, said compounds having an improved efficiency and/or an improved solubility and/or an improved toxicity and/or an improved in vivo stability and/or an improved biodisponibility and/or said compounds being easier to synthesize at an industrial scale.
Another object of the present invention is to provide compounds that can be active, when orally administered.
Another object of the invention is to provide compounds able to interact and/or react with VCP/p97.
Another object of the present invention is to provide a pharmaceutical composition comprising the compounds of the present invention. Advantageously, this composition can be orally administered.